EFFICACY OF SULOFENUR AND A 2ND-GENERATION DIARYLSULFONYLUREA, ROBENZOFURYL)SULFONYL]-N'-(3,4-DICHLOROPHENYL)UREA (LY295501), AGAINST COLONADENOCARCINOMA XENOGRAFTS

Sulofenur and a second generation diarylsulfonylurea (DSU), N-[5-(2,3- dihydrobenzofuryl)sulfonyl]-N' chlorophenyl)urea (LY295501), were eval uated against a panel of eight colon adenocarcinoma xenografts. Of the se tumors, four were derived from adult patients and four from young p atients (age range 11-26 years). Both drugs were administered twice da ily by oral gavage, 5 days each week for two or three consecutive week s. The maximum tolerated dose for sulofenur was 300 mg/kg/dose for thr ee courses and 200 mg/kg/dose for LY295501. Against 'adult' derived tu mors, sulofenur caused a high proportion of objective regressions of a dvanced xenografts in two of four lines, with significant inhibition o f growth in three tumor lines. Colon adenocarcinomas from young patien ts were similarly sensitive to sulofenur with a high proportion of com plete and partial responses in two of three lines. LY295501 demonstrat ed a very similar spectrum of activity against this panel of xenograft s. Tumors intrinsically resistant to sulofenur were resistant to LY295 501, although this agent was slightly more active than sulofenur again st tumors from younger patients. In addition, xenografts were establis hed from a cloned colon adenocarcinoma line (GC(3)/c1) and its derivat ive (GC(3)/LYC5) selected in vitro for resistance to sulofenur. GC(3)/ c1 xenografts were highly responsive to both sulofenur and LY295501, w hereas GC(3)/LYC5 xenografts were completely resistant to both agents administered at the maximum tolerated dose and schedule. These results indicate that the second generation DSU, LY295501, demonstrates a sim ilar spectrum of activity against colon tumors as does sulofenur, and that the mechanism of action and/or resistance to the two drugs is pro bably similar.